Shimomura I, Funahashi T, Takahashi M, et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med. Hotamisligil GS, Shargill NS, Spiegelman BM.

Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Arkan MC, Hevener AL, Greten FR, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance.

Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha.

Tripathy D, Mohanty P, Dhindsa S, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Summers SA.

Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X.

Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Trujillo ME, Scherer PE. Adipose tissue-derived factors: impact on health and disease. Wellen KE, Hotamisligil GS.

Inflammation, stress, and diabetes. Chaudhuri A, Janicke D, Wilson MF, et al. Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults.

Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population NHANES Goday A, Calvo E, Vázquez LA, et al.

BMC Public Health. Article PubMed PubMed Central Google Scholar. Stefan N, Kantartzis K, Machann J, et al. Identification and characterization of metabolically benign obesity in humans. Hinnouho GM, Czernichow S, Dugravot A, et al.

Metabolically healthy obesity and the risk of cardiovascular disease and type 2 diabetes: the Whitehall II cohort study. Eur Heart J. Kannel WB, McGee DL.

Diabetes and cardiovascular disease. The Framingham study. Hu FB, Stampfer MJ, Solomon CG, et al. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.

Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. Facchini FS, Hua N, Abbasi F, Reaven GM.

Insulin resistance as a predictor of age-related diseases. Nosadini R, Manzato E, Solini A, et al. Peripheral, rather than hepatic, insulin resistance and atherogenic lipoprotein phenotype predict cardiovascular complications in NIDDM.

Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study.

Robins SJ, Rubins HB, Faas FH, et al. Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial VA-HIT. Kuusisto J, Lempiäinen P, Mykkänen L, Laakso M. Insulin resistance syndrome predicts coronary heart disease events in elderly type 2 diabetic men.

Hu G, Qiao Q, Tuomilehto J, et al. Plasma insulin and cardiovascular mortality in non-diabetic European men and women: a meta-analysis of data from eleven prospective studies. Resnick HE, Jones K, Ruotolo G, et al. Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic American Indians: the Strong Heart Study.

Rutter MK, Meigs JB, Sullivan LM, D'Agostino RB, Wilson PW. Insulin resistance, the metabolic syndrome, and incident cardiovascular events in the Framingham Offspring Study. Ruige JB, Assendelft WJ, Dekker JM, Kostense PJ, Heine RJ, Bouter LM.

Insulin and risk of cardiovascular disease: a meta-analysis. Folsom AR, Szklo M, Stevens J, Liao F, Smith R, Eckfeldt JH. A prospective study of coronary heart disease in relation to fasting insulin, glucose, and diabetes. The Atherosclerosis Risk in Communities ARIC Study.

Folsom AR, Rasmussen ML, Chambless LE, et al. Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The Atherosclerosis Risk in Communities ARIC Study Investigators. Pyörälä M, Miettinen H, Laakso M, Pyörälä K. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the year follow-up results of the Helsinki Policemen Study.

Yarnell JW, Patterson CC, Bainton D, Sweetnam PM. Is metabolic syndrome a discrete entity in the general population? Evidence from the Caerphilly and Speedwell population studies. Hyperinsulinemia and the risk of stroke in healthy middle-aged men: the year follow-up results of the Helsinki Policemen Study.

Welin L, Bresäter LE, Eriksson H, Hansson PO, Welin C, Rosengren A. Insulin resistance and other risk factors for coronary heart disease in elderly men. The Study of Men Born in and Eur J Cardiovasc Prev Rehabil. Sarwar N, Sattar N, Gudnason V, Danesh J.

Circulating concentrations of insulin markers and coronary heart disease: a quantitative review of 19 Western prospective studies. Chen W, Srinivasan SR, Li S, Xu J, Berenson GS.

Metabolic syndrome variables at low levels in childhood are beneficially associated with adulthood cardiovascular risk: the Bogalusa Heart Study. Modan M, Halkin H, Almog S, et al. A link between hypertension obesity and glucose intolerance.

Reaven GM, Lerner RL, Stern MP, Farquhar JW. Role of insulin in endogenous hypertriglyceridemia. Jeppesen J, Hollenbeck CB, Zhou MY, et al.

Relation between insulin resistance, hyperinsulinemia, postheparin plasma lipoprotein lipase activity, and postprandial lipemia. Arterioscler Thromb Vasc Biol.

Tobey TA, Greenfield M, Kraemer F, Reaven GM. Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics, and plasma triglyceride levels in normotriglyceridemic man. Zavaroni I, Bonora E, Pagliara M, et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance.

Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. J Am Coll Nutr. Expert Panel on Detection Ea, Treatment of High Blood Cholesterol in Adults.

Executive summary of the third report of The National Cholesterol Education Program NCEP expert panel on detection, evaluation, and treatment of high blood cholesterol in adults adult treatment panel III. Alberti KG, Eckel RH, Grundy SM, et al.

Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.

Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. Diabet Med. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications.

Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Einhorn D, Reaven GM, Cobin RH, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract. PubMed Google Scholar.

Grundy SM, Cleeman JI, Daniels SR, et al. Crit Pathw Cardiol. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome —a new world-wide definition.

A Consensus Statement from the International Diabetes Federation. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.

S Adults. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics update: a report from the American Heart Association. Beltrán-Sánchez H, Harhay MO, Harhay MM, McElligott S.

Prevalence and trends of metabolic syndrome in the adult U. population, — Wilson PW, Meigs JB, Sullivan L, Fox CS, Nathan DM, D'Agostino RB.

Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Lorenzo C, Williams K, Hunt KJ, Haffner SM. The National Cholesterol Education Program — Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes.

Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence.

Wang J, Ruotsalainen S, Moilanen L, Lepistö P, Laakso M, Kuusisto J. The metabolic syndrome predicts cardiovascular mortality: a year follow-up study in elderly non-diabetic Finns.

Nilsson PM, Engström G, Hedblad B. The metabolic syndrome and incidence of cardiovascular disease in non-diabetic subjects — a population-based study comparing three different definitions.

Katzmarzyk PT, Janssen I, Ross R, Church TS, Blair SN. The importance of waist circumference in the definition of metabolic syndrome: prospective analyses of mortality in men. Qiao Q, Group DS. Comparison of different definitions of the metabolic syndrome in relation to cardiovascular mortality in European men and women.

Sattar N, McConnachie A, Shaper AG, et al. Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies.

van Herpt TT, Dehghan A, van Hoek M, et al. The clinical value of metabolic syndrome and risks of cardiometabolic events and mortality in the elderly: the Rotterdam study. Cardiovasc Diabetol. Guzder RN, Gatling W, Mullee MA, Byrne CD. Impact of metabolic syndrome criteria on cardiovascular disease risk in people with newly diagnosed type 2 diabetes.

Bonora E, Targher G, Formentini G, et al. The Metabolic Syndrome is an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Prospective data from the Verona Diabetes Complications Study. Tong PC, Kong AP, So WY, et al.

Sone H, Mizuno S, Fujii H, et al. Is the diagnosis of metabolic syndrome useful for predicting cardiovascular disease in Asian diabetic patients? Analysis from the Japan Diabetes Complications Study.

Bruno G, Merletti F, Biggeri A, et al. Metabolic syndrome as a predictor of all-cause and cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study. Cull CA, Jensen CC, Retnakaran R, Holman RR. Impact of the metabolic syndrome on macrovascular and microvascular outcomes in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP, Study SAH.

National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults.

Stern MP, Williams K, Hunt KJ. Atheroscler Suppl. Stern MP, Williams K, González-Villalpando C, Hunt KJ, Haffner SM. Cheal KL, Abbasi F, Lamendola C, McLaughlin T, Reaven GM, Ford ES. Relationship to insulin resistance of the adult treatment panel III diagnostic criteria for identification of the metabolic syndrome.

Liao Y, Kwon S, Shaughnessy S, et al. Critical evaluation of adult treatment panel III criteria in identifying insulin resistance with dyslipidemia. Meigs JB, Rutter MK, Sullivan LM, Fox CS, D'Agostino RB, Wilson PW. Impact of insulin resistance on risk of type 2 diabetes and cardiovascular disease in people with metabolic syndrome.

The metabolic syndrome: time to get off the merry-go-round? J Intern Med. Download references. You can also search for this author in PubMed Google Scholar.

Correspondence to Mary Ann Banerji or Milay Luis Lam. Lenox Hill Hospital Division of Endocrinology, New York, New York, USA. Reprints and permissions. Banerji, M. Insulin Resistance and the Metabolic Syndrome.

In: Poretsky, L. eds Principles of Diabetes Mellitus. Springer, Cham. Received : 27 June Accepted : 27 June Published : 18 August Publisher Name : Springer, Cham. Online ISBN : eBook Packages : Springer Reference Medicine Reference Module Medicine. Policies and ethics.

Skip to main content. References Reaven G. Article PubMed Google Scholar Defronzo RA. Article CAS PubMed PubMed Central Google Scholar Bergman RN, Finegood DT, Kahn SE.

Article CAS PubMed Google Scholar Taguchi A, White MF. Article CAS PubMed Google Scholar Taniguchi CM, Emanuelli B, Kahn CR. Article CAS PubMed Google Scholar Chen Y, Zhu J, Lum PY, et al. Article CAS PubMed PubMed Central Google Scholar Muoio DM, Newgard CB.

Article CAS PubMed Google Scholar Reaven GM. Article CAS PubMed Google Scholar Lebovitz HE. Article CAS PubMed Google Scholar Cusi K, Maezono K, Osman A, et al. Article CAS PubMed PubMed Central Google Scholar Schwartz EA, Reaven PD.

Article CAS PubMed Google Scholar Fröjdö S, Vidal H, Pirola L. Article PubMed CAS Google Scholar Leroith D, Accili D. Article CAS PubMed PubMed Central Google Scholar DeFronzo RA, Tobin JD, Andres R.

CAS PubMed Google Scholar Sherwin RS, Kramer KJ, Tobin JD, et al. Article CAS PubMed PubMed Central Google Scholar Shen SW, Reaven GM, Farquhar JW.

Article CAS PubMed PubMed Central Google Scholar Bergman RN, Phillips LS, Cobelli C. Article CAS PubMed PubMed Central Google Scholar Bergman RN, Prager R, Volund A, Olefsky JM.

Article CAS PubMed PubMed Central Google Scholar Bergman RN, Ider YZ, Bowden CR, Cobelli C. CAS PubMed Google Scholar Yang YJ, Youn JH, Bergman RN. CAS PubMed Google Scholar Beard JC, Bergman RN, Ward WK, Porte D. Metabolic syndrome is closely associated with insulin resistance, in which cells fail to respond appropriately to insulin, a hormone that regulates multiple cell metabolic processes such as taking up sugar from the blood.

But thus far, scientists have been unable to understand how insulin resistance might produce the different features of metabolic syndrome.

Finally, a new study puts the pieces together. It involves a surprise pairing of two infamous molecules, with diet and gut microbes playing supporting roles. Over past five years, studies have found an increase in a compound called TMAO in people with insulin resistance, diabetes, kidney disease, cardiovascular disease, and neurodegenerative disease.

Mice fed TMAO have been found to develop glucose intolerance, thrombosis, kidney disease and neurodegenerative disease. We wanted to know how this molecule works. The study, published September 19 in Cell Metabolism , identified, for the first time, what cellular receptor TMAO uses to exert its effects: a molecule called PERK.

PERK is a linchpin of stress signaling within cells — specifically, stress on the endoplasmic reticulum ER , a part of the cell where proteins are assembled, folded, and dispatched to do their jobs.

Under conditions of ER stress, misfolded proteins accumulate and PERK sends distress signals that can ultimately trigger cell death pathways. The interplay between TMAO and PERK could give a new framework for understanding insulin resistance and metabolic syndrome, and the host of diseases they predispose us to — stroke, heart attack, kidney failure and more, says Biddinger.

GLUT4 is mostly present in the intracellular vesicles at resting stages and is translocated to the plasma membrane upon insulin stimulation [ ].

After uptake, free glucose is rapidly phosphorylated to glucose 6-phosphate G6P , which subsequently enters many metabolic pathways [ 13 ]. Glycolysis represents the major pathway in glucose and yields pyruvate for subsequent oxidation.

Beside glycolysis, G6P also may be channeled into glycogen synthesis or the pentose phosphate pathway PPP. The PPP is an important source of NADPH, which plays a critical role in regulating cellular oxidative stress and is required for lipid synthesis [ ]. In response to an increased energy demand, heart muscle cells initially rely on carbohydrate oxidation.

For example, under stress such as exercise, ischemia and pathological hypertrophy, the substrate preference of glucose can be changed [ ]. Under stress, a rapid increase in GLUT4 expression is an early adaptive response that suggests the physiological role of this adaptation is to enhance the replenishment of muscle glycogen stores.

When glycogen content is high, the heart preferentially uses glycogen as a source, but when glycogen stores are low, it changes to fatty acid oxidation.

This induction can be prevented by a high carbohydrate diet during recovery. The control of metabolism in recovery by glycogen levels underlines its importance as the metabolic muscles reserve [ ].

In insulin resistance, the heart is embedded in a rich fatty acid and glucose environment [ , , ]. An excess of insulin promotes increased uptake of FFA in the heart due to up regulation of the cluster differentiation protein 36 CD36 [ ], which is a potent FFA transporter; this increases intracellular fatty acids levels and PPAR-α expression.

The latter, increases the gene expression in the three stages of fatty acid oxidation by increasing the synthesis of 1 FFA transporters in the cell, 2 proteins that imports FFA to the mitochondrium, and 3 enzymes in the fatty acid oxidation [ ].

On the other hand, due to the inhibition of glucose utilization, a glycolytic intermediate accumulates in the cardiomyocytes, which induces glucotoxicity. Furthermore, when diabetes progresses or when additional stresses are posed on the heart; metabolic mal-adaptation can occur and there is a great loss of metabolic flexibility [ ].

The heart decreases its ability to use fatty acids, increasing FFA delivery, and leading to intramyocardial lipid accumulation ceramides, diacylglycerols, long-chain acyl-CoAs, and acylcarnitines [ ]. This lipid accumulation may contribute to apoptosis, impairing mitochondrial function, cardiac hypertrophy, and contractile dysfunction [ , ] Fig.

For example, diacylglycerol and fatty acyl-coenzyme CoA induce activation of atypical PKC, which results in impaired insulin signal transduction [ ]. Ceramides act as key components of lipotoxic signaling pathways linking lipid-induced inflammation with insulin signaling inhibition [ ]. On other hand, high lipid contents can induce contractile dysfunction independently of insulin resistance [ ].

Therefore, the resultant defect in myocardial energy production impairs myocyte contraction and diastolic function [ 93 , ] Fig. These alterations produce functional changes that lead to cardiomyopathy and heart failure [ , , , ].

In uncontrolled diabetes, the body goes from the fed to the fasted state and the liver switches from carbohydrate or lipid utilization to ketone production in response to low insulin levels and high levels of counter-regulatory hormones [ ]. The ketone bodies generated in the liver enter in the blood stream and are used by other organs, such as the brain, kidneys, skeletal muscle, and heart.

Disruptions in myocardial fuel metabolism and bioenergetics contribute to cardiovascular disease as the adult heart requires high energy for contractile function [ ]. In this situation, the heart uses alternative pathways such as ketone bodies as fuel for oxidative ATP production [ ].

However, there is still controversy around whether this fuel shift is adaptive or maladaptive. The ketogenic diet effect can be mediated by suppressing longevity-related insulin signaling and mTOR pathway, and activation of peroxisome proliferator activated receptor α PPARα , the master regulator that switches on genes involved in ketogenesis [ ].

Several reports suggest that ketogenic diet may be associated with a decreased incidence of risk factors of cardiovascular disease such obesity, diabetes, arterial blood pressure and cholesterol levels, but these effects are usually limited in time [ ].

However other reports indicated that cardiac risk factor reductions corresponded with weight loss regardless of a type of diet used [ ]. Excessive production of ROS leads to protein, DNA, and membrane damage.

In addition, ROS exerts deleterious effects on the endoplasmic reticulum. This also contributes to diabetic cardiomyopathy pathogenesis [ , ]. Insulin essentially provides an integrated set of signals allowing the balance between nutrient demand and availability. Impaired nutrition contributes to hyperlipidemia and insulin resistance causing hyperglycemia.

This condition alters cellular metabolism and intracellular signaling that negatively impact cells. In the cardiomyocyte, this damage can be summarized into three actions: 1 alteration in insulin signaling.

All these effects induce cellular events including: 1 gene expression modifications, 2 hyperglycemia and dyslipidemia, 3 activation of oxidative stress and inflammatory response, 4 endothelial dysfunction, and 5 ectopic lipid accumulation, which, favored by obesity, perpetuates the metabolic deregulation.

Overall, insulin resistance contributes to generate CVD via two independent pathways: 1 atheroma plaque formation and 2 ventricular hypertrophy and diastolic abnormality.

Both effects lead to heart failure. Future research is needed to understand the precise mechanism between insulin resistance and its progression to heart failure with a focus on new therapy development. Steinberger J, Daniels SR, American Heart Association Atherosclerosis H, Obesity in the Young C, American Heart Association Diabetes C.

Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee Council on Cardiovascular Disease in the Young and the Diabetes Committee Council on Nutrition, Physical Activity, and Metabolism.

Article PubMed Google Scholar. Steinberger J, Moorehead C, Katch V, Rocchini AP. Relationship between insulin resistance and abnormal lipid profile in obese adolescents. J Pediatr. Article PubMed CAS Google Scholar.

Ferreira AP, Oliveira CE, Franca NM. Metabolic syndrome and risk factors for cardiovascular disease in obese children: the relationship with insulin resistance HOMA-IR.

Jornal de pediatria. Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol. Wilcox G. Insulin and insulin resistance.

Clin Biochem Rev. PubMed PubMed Central Google Scholar. Gast KB, Tjeerdema N, Stijnen T, Smit JW, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS ONE. Article PubMed PubMed Central CAS Google Scholar. Bornfeldt KE, Tabas I.

Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. Davidson JA, Parkin CG. Is hyperglycemia a causal factor in cardiovascular disease?

Does proving this relationship really matter? Diabetes Care. Article PubMed PubMed Central Google Scholar. Laakso M, Kuusisto J. Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol. Janus A, Szahidewicz-Krupska E, Mazur G, Doroszko A. Insulin resistance and endothelial dysfunction constitute a common therapeutic target in cardiometabolic disorders.

Mediators Inflamm. Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway.

Proc Natl Acad Sci USA. Bogan JS. Regulation of glucose transporter translocation in health and diabetes. Annu Rev Biochem. Zimmer HG. Regulation of and intervention into the oxidative pentose phosphate pathway and adenine nucleotide metabolism in the heart. Mol Cell Biochem. Choi SM, Tucker DF, Gross DN, Easton RM, DiPilato LM, Dean AS, Monks BR, Birnbaum MJ.

Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol Cell Biol. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS.

Regulation of lipolysis in adipocytes. Annu Rev Nutr. Czech MP, Tencerova M, Pedersen DJ, Aouadi M.

Insulin signalling mechanisms for triacylglycerol storage. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Investig. Hojlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

Dan Med J. PubMed Google Scholar. Kahn BB, Flier JS. Obesity and insulin resistance. Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract.

Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. Wu G, Meininger CJ. Nitric oxide and vascular insulin resistance. BioFactors Oxford, England. Article CAS Google Scholar. Wang CC, Gurevich I, Draznin B. Insulin affects vascular smooth muscle cell phenotype and migration via distinct signaling pathways.

Berg J, Tymoczko J, Stryer L: Food intake and starvation induce metabolic changes. In: Biochemistry. Catalano PM. Obesity, insulin resistance and pregnancy outcome. Reproduction Cambridge, England. Bonora E. Insulin resistance as an independent risk factor for cardiovascular disease: clinical assessment and therapy approaches.

Av Diabetol. Google Scholar. Goodwin PJ, Ennis M, Bahl M, Fantus IG, Pritchard KI, Trudeau ME, Koo J, Hood N. High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome.

Breast Cancer Res Treat. Seriolo B, Ferrone C, Cutolo M. Longterm anti-tumor necrosis factor-alpha treatment in patients with refractory rheumatoid arthritis: relationship between insulin resistance and disease activity. J Rheumatol. PubMed CAS Google Scholar.

Williams T, Mortada R, Porter S. Diagnosis and treatment of polycystic ovary syndrome. Am Fam Physician. Lallukka S, Yki-Jarvinen H. Non-alcoholic fatty liver disease and risk of type 2 diabetes. Best Pract Res Clin Endocrinol Metab.

Rader DJ. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med. Wende AR, Abel ED. Lipotoxicity in the heart.

Biochem Biophys Acta. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Wang CC, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology.

Moller DE, Kaufman KD. Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med. Matthaei S, Stumvoll M, Kellerer M, Haring HU. Pathophysiology and pharmacological treatment of insulin resistance.

Endocr Rev. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, et al.

Insulin resistance and growth retardation in mice lacking insulin receptor substrate Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, et al. Disruption of IRS-2 causes type 2 diabetes in mice.

Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB 3rd, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ.

Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 PKB beta. Saini V. Molecular mechanisms of insulin resistance in type 2 diabetes mellitus.

World J Diabetes. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, et al. Effects of free fatty acids on glucose transport and IRSassociated phosphatidylinositol 3-kinase activity.

Sinha R, Dufour S, Petersen KF, LeBon V, Enoksson S, Ma YZ, Savoye M, Rothman DL, Shulman GI, Caprio S. Assessment of skeletal muscle triglyceride content by 1 H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity.

Unger RH, Orci L. Lipotoxic diseases of nonadipose tissues in obesity. Int J Obes Related Metab Dis. Dong B, Qi D, Yang L, Huang Y, Xiao X, Tai N, Wen L, Wong FS.

TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes. Am J Physiol Heart Circ Physiol. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr.

Obesity is associated with macrophage accumulation in adipose tissue. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.

Draznin B. Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85 alpha—the two sides of a coin. Tremblay F, Krebs M, Dombrowski L, Brehm A, Bernroider E, Roth E, Nowotny P, Waldhausl W, Marette A, Roden M.

Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Chiang GG, Abraham RT. Phosphorylation of mammalian target of rapamycin mTOR at ser is mediated by p70S6 kinase. J Biol Chem. Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J.

Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol. Aroor AR, Mandavia CH, Sowers JR. Insulin resistance and heart failure: molecular mechanisms. Heart Fail Clin. Flegal KM, Graubard BI, Williamson DF, Gail MH.

Excess deaths associated with underweight, overweight, and obesity. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Liu L, Feng J, Zhang G, Yuan X, Li F, Yang T, Hao S, Huang D, Hsue C, Lou Q.

Visceral adipose tissue is more strongly associated with insulin resistance than subcutaneous adipose tissue in Chinese subjects with pre-diabetes. Curr Med Res Opin. Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease.

N Engl J Med. Lalia AZ, Dasari S, Johnson ML, Robinson MM, Konopka AR, Distelmaier K, Port JD, Glavin MT, Esponda RR, Nair KS, et al. Predictors of whole-body insulin sensitivity across ages and adiposity in adult humans.

J Clin Endocrinol Metab. Gonzalez N, Moreno-Villegas Z, Gonzalez-Bris A, Egido J, Lorenzo O. Regulation of visceral and epicardial adipose tissue for preventing cardiovascular injuries associated to obesity and diabetes.

Cardiovasc Diabetol. Kim JI, Huh JY, Sohn JH, Choe SS, Lee YS, Lim CY, Jo A, Park SB, Han W, Kim JB. Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation. Alman AC, Smith SR, Eckel RH, Hokanson JE, Burkhardt BR, Sudini PR, Wu Y, Schauer IE, Pereira RI, Snell-Bergeon JK.

The ratio of pericardial to subcutaneous adipose tissues is associated with insulin resistance. Obesity Silver Spring, Md. Fitzgibbons TP, Czech MP.

Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J Am Heart Assoc. Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.

Nat Rev Mol Cell Biol. Iacobellis G, Ribaudo MC, Zappaterreno A, Iannucci CV, Leonetti F. Relation between epicardial adipose tissue and left ventricular mass.

Am J Cardiol. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, Romijn JA, de Roos A, Lamb HJ. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus.

J Am Coll Cardiol. Nyman K, Granér M, Pentikäinen MO, Lundbom J, Hakkarainen A, Sirén R, Nieminen MS, Taskinen M-R, Lundbom N, Lauerma K. Cardiac steatosis and left ventricular function in men with metabolic syndrome. J Cardiovasc Magn Reson.

Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M. Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Insulin sensitivity and atherosclerosis.

The Insulin Resistance Atherosclerosis Study IRAS Investigators. Tenenbaum A, Adler Y, Boyko V, Tenenbaum H, Fisman EZ, Tanne D, Lapidot M, Schwammenthal E, Feinberg MS, Matas Z, et al. Insulin resistance is associated with increased risk of major cardiovascular events in patients with preexisting coronary artery disease.

Am Heart J. Eddy D, Schlessinger L, Kahn R, Peskin B, Schiebinger R. Relationship of insulin resistance and related metabolic variables to coronary artery disease: a mathematical analysis.

Savaiano DA, Story JA. Cardiovascular disease and fiber: is insulin resistance the missing link? Nutr Rev. Kong C, Elatrozy T, Anyaoku V, Robinson S, Richmond W, Elkeles RS. Insulin resistance, cardiovascular risk factors and ultrasonically measured early arterial disease in normotensive Type 2 diabetic subjects.

Diabetes Metab Res Rev. Ginsberg HN. Insulin resistance and cardiovascular disease. Bloomgarden ZT. Insulin resistance, dyslipidemia, and cardiovascular disease.

Kozakova M, Natali A, Dekker J, Beck-Nielsen H, Laakso M, Nilsson P, Balkau B, Ferrannini E. Insulin sensitivity and carotid intima-media thickness: relationship between insulin sensitivity and cardiovascular risk study.

Min J, Weitian Z, Peng C, Yan P, Bo Z, Yan W, Yun B, Xukai W. Correlation between insulin-induced estrogen receptor methylation and atherosclerosis.

Chanda D, Luiken JJ, Glatz JF. Signaling pathways involved in cardiac energy metabolism. FEBS Lett. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH.

Lipotoxic heart disease in obese rats: implications for human obesity. Ramírez E, Picatoste B, González-Bris A, Oteo M, Cruz F, Caro-Vadillo A, Egido J, Tuñón J, Morcillo MA, Lorenzo Ó. Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in experimental type-II diabetes: role of GLP-1 isoforms in Glut4 receptor trafficking.

Goldberg IJ. Clinical review diabetic dyslipidemia: causes and consequences. Sparks JD, Sparks CE, Adeli K. Selective hepatic insulin resistance, VLDL overproduction, and hypertriglyceridemia. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Austin MA, Hokanson JE, Edwards KL.

Hypertriglyceridemia as a cardiovascular risk factor. Hokanson JE. Hypertriglyceridemia and risk of coronary heart disease. Curr Cardiol Rep. Sung KC, Park HY, Kim MJ, Reaven G. Metabolic markers associated with insulin resistance predict type 2 diabetes in Koreans with normal blood pressure or prehypertension.

Ginsberg HN, Zhang YL, Hernandez-Ono A. Metabolic syndrome: focus on dyslipidemia. Yadav R, Hama S, Liu Y, Siahmansur T, Schofield J, Syed AA, France M, Pemberton P, Adam S, Ho JH, et al.

Effect of Roux-en-Y bariatric surgery on lipoproteins, insulin resistance, and systemic and vascular inflammation in obesity and diabetes. Front Immunol. de Luca C, Olefsky JM. Inflammation and insulin resistance. den Boer MA, Voshol PJ, Kuipers F, Romijn JA, Havekes LM.

Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production. Am J Physiol Endocrinol Metab. Semenkovich CF. Insulin resistance and atherosclerosis. Lewis GF, Steiner G. Acute effects of insulin in the control of VLDL production in humans.

Implications for the insulin-resistant state. Haas ME, Attie AD, Biddinger SB. The regulation of ApoB metabolism by insulin.

Trends Endocrinol Metab. Verges B. Pathophysiology of diabetic dyslipidaemia: where are we? Pont F, Duvillard L, Florentin E, Gambert P, Verges B.

Early kinetic abnormalities of apoB-containing lipoproteins in insulin-resistant women with abdominal obesity. Hoogeveen RC, Gaubatz JW, Sun W, Dodge RC, Crosby JR, Jiang J, Couper D, Virani SS, Kathiresan S, Boerwinkle E, et al.

Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk in Communities ARIC study.

Packard CJ. Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein. Biochem Soc Trans. Sandhofer A, Kaser S, Ritsch A, Laimer M, Engl J, Paulweber B, Patsch JR, Ebenbichler CF. Cholesteryl ester transfer protein in metabolic syndrome.

Rashid S, Watanabe T, Sakaue T, Lewis GF. Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity.

Clin Biochem. von Bibra H, Saha S, Hapfelmeier A, Muller G, Schwarz PEH. Kim MK, Ahn CW, Kang S, Nam JS, Kim KR, Park JS.